Tetrahydroindolone Derivatives for Treament of Neurological Conditions

ABSTRACT

Compositions comprising tetrahydroindolone derivatives in which the tetrahydroindolone moiety is covalently linked to a substituted arylpiperazine moiety and methods for treating neurological and psychiatric conditions using such compositions are disclosed.

This application claims priority from U.S. Provisional PatentApplication No. 60/505,692 filed on Sep. 25, 2003, entitled “Compositionand method for treating pain and pain-induced psychiatric disorders.”

BACKGROUND

Psychiatric and neurological conditions can be extremely difficult totreat effectively because of the multiplicity of symptoms and etiologiesassociated with such conditions. Current drug therapies have focused oneither high selectivity for one pharmacological effect or broadnon-selectivity to attempt to provide multiple symptom relief. Therapiesthat have focused on high pharmacological selectivity have been shown toprovide limited benefits for disorders with multiple causes, but can insome cases worsen some symptoms. For example, selective antagonism ofdopaminergic receptors for schizophrenia results in a worsening of somenegative symptoms as well as in tardive dyskinesia.

Drug therapies having broad non-selectivity, on the other hand, canprovide relief for more symptoms but often have more side effects. Forinstance, current antipyschotic drugs have adrenergic, cholinergic, andhistaminergic receptor antagonist activities that are associated withdeterioration of cognitive function and other side-effects, such asorthostatic hypotension, dry mouth, blurred vision, constipation, andmotor impairment. Regardless of drug therapy selectivity, there remainsymptoms, such as cognitive decline, that are not adequately treated bycurrent pharmaceutical compounds used in treating psychiatric andneurological conditions. A need therefore remains for improvedpharmaceutical compounds for use in treating such conditions.

SUMMARY

We have discovered that the combination tetrahydroindolonearylpiperazine compounds described herein can be useful for treatingmany different psychiatric and neurological conditions, including butnot limited to pain, emesis, neurodegeneration including neuropathies,and psychiatric disorders, as described below.

DETAILED DESCRIPTION

Definitions

As used herein, the following terms have the following meanings, unlessexplicitly stated otherwise.

The term “alkyl” refers to saturated aliphatic groups includingstraight-chain, branched-chain, and cyclic groups, all of which can beoptionally substituted. Preferred alkyl groups contain 1 to 10 carbonatoms. Suitable alkyl groups include methyl, ethyl, and the like, andcan be optionally substituted. The term “heteroalkyl” refers tocarbon-containing straight-chained, branch-chained and cyclic groups,all of which can be optionally substituted, containing at least one O, Nor S heteroatoms. The term “alkoxy” refers to the ether —O-alkyl, wherealkyl is defined as above.

The term “alkenyl” refers to unsaturated groups which contain at leastone carbon-carbon double bond and includes straight-chain,branched-chain, and cyclic groups, all of which can be optionallysubstituted. Preferable alkenyl groups have 2 to 10 carbon atoms. Theterm “heteroalkenyl” refers to unsaturated groups which contain at leastone carbon-carbon double bond and includes straight-chained,branch-chained and cyclic groups, all of which can be optionallysubstituted, containing at least one O, N or S heteroatoms.

The term “aryl” refers to aromatic groups that have at least one ringhaving a conjugated, pi-electron system and includes carbocyclic aryland biaryl, both of which can be optionally substituted. Preferred arylgroups have 6 to 10 carbon atoms. The term “aralkyl” refers to an alkylgroup substituted with an aryl group. Suitable aralkyl groups includebenzyl and the like; these groups can be optionally substituted. Theterm “aralkenyl” refers to an alkenyl group substituted with an arylgroup. The term “heteroaryl” refers to carbon-containing 5-14 memberedcyclic unsaturated radicals containing one, two, three, or four O, N, orS heteroatoms and having 6, 10, or 14-electrons delocalized in one ormore rings, e.g., pyridine, oxazole, indole, thiazole, isoxazole,pyrazole, pyrrole, each of which can be optionally substituted asdiscussed above.

The term “sulfonyl” refers to the group —S(O₂)—. The term “halo” refersto fluoro-, chloro-, bromo-, or iodo-substitutions. The term “alkanoyl”refers to the group —C(O)Rg, where Rg is alkyl. The term “aroyl” refersto the group —C(O)Rg, where Rg is aryl. Similar compound radicalsinvolving a carbonyl group and other groups are defined by analogy. Theterm “aminocarbonyl” refers to the group —NHC(O)—. The term“oxycarbonyl” refers to the group —OC(O)—. The term “heteroaralkyl”refers to an alkyl group substituted with a heteroaryl group. Similarly,the term “heteroaralkenyl” refers to an alkenyl group substituted with aheteroaryl group.

The term “optionally substituted” refers to one or more substituentswhich can be, without limitation, alkyl, aryl, amino, hydroxy, alkoxy,aryloxy, alkylamino, arylamino, alkylthio, arylthio, or oxo, cyano,acetoxy, or halo moieties.

As used herein, the term “derivative” refers to a compound that ismodified or partially substituted with another component. Additionally,the term “derivative” encompasses compounds that can be structurallysimilar but can have similar or different functions. The term“pharmacophore” refers to a structural component of a molecule thatcauses a pharmacological response. The terms “patient,” “subject” andthe like with reference to individuals that can be treated with thepresent compounds and/or pharmaceutical compositions refer to humans andother mammals.

The terms “a,” “an,” and “the” and similar referents used in the contextof describing the present invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context. Recitation of value ranges herein ismerely intended to serve as a shorthand method for referringindividually to each separate value falling within the range. Unlessotherwise indicated herein, each individual value is incorporated intothe specification as if it were individually recited herein.

Compounds

The compounds of the present invention have the general schematicstructure {A}-L-{B}, where A is a tetrahydroindolone derivative, L is ahydrocarbyl chain, and B is an arylpiperazine derivative, as describedbelow.

Tetrahydroindolone Derivatives

In the compounds of the present invention, the tetrahydroindolonederivatives (“THI”) have the structure of formula (I) below:

where:(a) X is CH or N;(b) R₁ is hydrogen, alkyl, aralky, heteroaralkyl, alkenyl, aralkenyl,heteroaralkenyl, aryl, or heteroaryl;(c) R₂ is hydrogen, alkyl, aralky, aryl, or heteroaryl;(d) R_(2′) is hydrogen unless R₂ is methyl, in which case R_(2′) is alsomethyl; and(e) L and R₃ are as described below.

As shown in Formula (I), the THI moiety has a six-membered saturatedring fused to a five-membered aromatic ring. The five-membered aromaticring can have one or two nitrogen atoms as indicated, but thefive-membered aromatic ring always has a nitrogen atom at the1-position. Typically, the five-membered aromatic ring has one nitrogenatom as in tetrahydroindolone. This nitrogen atom at the 1-position iscovalently bonded to the linker L.

Typically, X is carbon in the tetrahydroindolone moiety. The THI moietycan be variously substituted, as described above. One example of such atetrahydroindolone moiety is a tetrahydroindolone moiety of formula (D)below:

where:(1) R₂ is hydrogen, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl;(2) R_(2′) is hydrogen unless R₂ is methyl, in which case R_(2′) is alsomethyl; and(3) L and R₃ are as described below.

In one particularly preferred embodiment, R₂ and R_(2′), are bothhydrogen. In this embodiment, the THI moiety is an unsubstitutedtetrahydroindolone moiety.

Arylpiperazine Moiety

The R3 group referred to above is an arylpiperazine moiety, which in thecompounds of the present invention has the structure of formula (III)below:

where:

-   -   (i) R₄ is hydrogen, alkyl, halo, hydroxy, alkoxy, cyano, nitro,        perfluoroalkyl, perfluoroalkoxy, or hydroxymethyl;    -   (i) R₅ is hydrogen, alkyl, halo, alkoxy, cyano, nitro,        perfluoroalkyl, perfluoroalkoxy, amino, aminocarbonyl,        aminosulfonyl, or hydroxymethyl;    -   (iii) R₆ is alkyl, halo, alkoxy, perfluoroalkyl,        perfluoroalkoxy, or nitro;    -   (iv) R₄ and R₅ when taken together can form a 5 or 6 membered        ring and can contain one or more heteroatoms; and    -   (v) R₅ and R₆ when taken together can form a 5 or 6 membered        ring and can contain one or more heteroatoms.

Preferably, the aryl piperazine moiety comprises one or more of thefollowing substitutions:

-   -   (i) R₄ is hydrogen, halo, or alkoxy;    -   (ii) R₅ is hydrogen, alkyl, halo, alkoxy, or perfluoroalkyl;    -   (iii) R₆ is alkyl, halo, alkoxy, or perfluoroalkyl;    -   (iv) R₄ and R₅ when taken together form a naphthalene ring; and    -   (v) R₅ and R₆ when taken together can be either a methylenedioxy        or ethylenedioxy group.        Linker Moiety

The linker moiety (L) used in the compounds of the present invention canbe a straight chain alkyl group of the formula —(CH₂)_(m)—, where m isan integer from 1 to 6 and more preferably either 3, 4, or 5.Alternatively, the linker can be an alkyl substituted hydrocarbyl moietyof the following formula (IV):

where:

-   -   (i) n is 0, 1 or 2;    -   (ii) R7 and R8 are hydrogen, methyl or ethyl;    -   (iii) R9 and R9′ are both hydrogen, methyl or ethyl;    -   (iv) if n is 1 and R7 or R8 is methyl or ethyl, then R9 and R9′        are hydrogen;    -   (v) if n is 1 and R7 and R8 are hydrogen, then R9 and R9′ are        methyl or ethyl; and    -   (vi) if n is 2, then R9 and R9′ are hydrogen and one or both of        R7 and R8 are methyl or ethyl.

The linker moiety can modulate properties of the present compounds. Forexample, a straight chain alkyl linker comprising two carbon atoms wouldprovide a more rigid linkage than a longer alkyl linker. Such rigiditycan produce greater specificity in target binding, while a less rigidlinker moiety can produce greater potency. The solubilitycharacteristics of the present compounds can also be affected by thenature of the linker moiety.

The use of a linker according to formula (IV) above is believed toprovide a more rigid linkage compared to a straight chain linker moietywith the same number of carbon atoms in the chain. This allows forfurther control over the properties of the present compounds.

Moreover, a linker according to formula (IV) can be used with compoundsother than those described herein which comprise a THI moiety (which canbe variously substituted) joined to an arylpiperazine moiety (which alsocan be variously substituted) via such a linker. Such THI moieties andother compounds are described, for example, in U.S. Pat. No. 6,770,638(the contents of which are hereby incorporated by reference).

Preferred Compounds

Table 1 below lists particularly preferred embodiments of the presentcompounds. TABLE 1 11-{2-[4-(4-Fluorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one21-{3-[4-(4-Fluorophenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one31-{4-[4-(4-Fluorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one41-{2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one51-{3-[4-(4-Chlorophenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one61-{4-[4-(4-Chlorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one71-{2-[4-(4-Methoxyphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one81-{3-[4-(4-Methoxyphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one91-{4-[4-(4-Methoxyphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one101-{2-[4-(4-Ethoxyphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one111-{3-[4-(4-Ethoxyphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one121-{4-[4-(4-Ethoxyphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one131-{2-[4-(4-Trifluoromethylphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one141-{3-[4-(4-Trifluoromethylphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one151-{4-[4-(4-Trifluoromethylphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one161-{2-[4-(4-Nitrophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one171-{3-[4-(4-Nitrophenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one181-{4-[4-(4-Nitrophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one19 1-{2-[4-p-Tolylpiperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one 201-{3-[4-p-Tolylpiperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one 211-{4-[4-p-Tolylpiperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one 221-{2-[4-(4-Trifluoromethoxyphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one231-{3-[4-(4-Trifluoromethoxyphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one241-{4-[4-(4-Trifluoromethoxyphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one251-{2-[4-(3,4-Dichlorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one261-{3-[4-(3,4-Dichlorophenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one271-{4-[4-(3,4-Dichlorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one281-{2-[4-(3,4-Difluorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one291-{3-[4-(3,4-Difluorophenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one301-{4-[4-(3,4-Difluorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one311-{2-[4-(3,4-Dimethylphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one321-{3-[4-(3,4-Dimethylphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one331-{4-[4-(3,4-Dimethylphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one341-{2-[4-(3,4-Dimethoxyphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one351-{3-[4-(3,4-Dimethoxyphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one361-{4-[4-(3,4-Dimethoxyphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one371-[2-(4-Benzo[1,3]dioxol-5-ylpiperazin-1-yl)ethyl]-1,5,6,7-tetrahydroindol-4-one381-[3-(4-Benzo[1,3]dioxol-5-ylpiperazin-1-yl)propyl]-1,5,6,7-tetrahydroindol-4-one391-[4-(4-Benzo[1,3]dioxol-5-ylpiperazin-1-yl)butyl]-1,5,6,7-tetrahydroindol-4-one401-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one411-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one421-{4-[4-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one431-{2-[4-(2,4-Dichlorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one441-{3-[4-(2,4-Dichlorophenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one451-{4-[4-(2,4-Dichlorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one461-{2-[4-(2,4-Difluorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one471-{3-[4-(2,4-Difluorophenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one481-{4-[4-(2,4-Difluorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one491-{2-[4-(2,4-Dimethylphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one501-{3-[4-(2,4-Dimethylphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one511-{4-[4-(2,4-Dimethylphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one521-{2-[4-(2,4-Dimethoxyphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one531-{3-[4-(2,4-Dimethoxyphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one541-{4-[4-(2,4-Dimethoxyphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one551-{2-[4-(2,3,4-Trichlorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one561-{3-[4-(2,3,4-Trichlorophenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one571-{4-[4-(2,3,4-Trichlorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one581-{2-[4-(2,3,4-Trifluorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one591-{3-[4-(2,3,4-Trifluorophenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one601-{4-[4-(2,3,4-Trifluorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one611-{2-[4-(3-Chloro-4-fluorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one621-{3-[4-(3-Chloro-4-fluorophenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one631-{4-[4-(3-Chloro-4-fluorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one641-{2-[4-(4-Fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one651-{3-[4-(4-Fluoro-3-trifluoromethylphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one661-{4-[4-(4-Fluoro-3-trifluoromethylphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one671-{2-[4-(4-Chloro-2-methoxyphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one681-{3-[4-(4-Chloro-2-methoxyphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one691-{4-[4-(4-Chloro-2-methoxyphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one701-{2-[4-(4-Chloro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one711-{3-[4-(4-Chloro-3-trifluoromethylphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one721-{4-[4-(4-Chloro-3-trifluoromethylphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one731-{2-[4-(3-Chloro-4-methoxyphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one741-{3-[4-(3-Chloro-4-methoxyphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one751-{4-[4-(3-Chloro-4-methoxyphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one761-{2-[4-(4-Methoxy-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one771-{3-[4-(4-Methoxy-3-trifluoromethylphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one781-{4-[4-(4-Methoxy-3-trifluoromethylphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one791-{2-[4-(4-Chloronaphthalen-1-yl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one801-{3-[4-(4-Chloronaphthalen-1-yl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one811-{4-[4-(4-Chloronaphthalen-1-yl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one821-{2-[4-(4-Trifluoromethylnaphthalen-1-yl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one831-{3-[4-(4-Trifluoromethylnaphthalen-1-yl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one841-{4-[4-(4-Trifluoromethylnaphthalen-1-yl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one851-{2-[4-(4-Chloro-2-fluorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one861-{3-[4-(4-Chloro-2-fluorophenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one871-{4-[4-(4-Chloro-2-fluorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one881-{2-[4-(4-Methoxy-2,3-dimethylphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one891-{3-[4-(4-Methoxy-2,3-dimethylphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one901-{4-[4-(4-Methoxy-2,3-dimethylphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-oneProperties

Preferred compounds of the present invention have a logP of from about 1to about 4 to enhance bioavailability and, when desired, central nervoussystem (CNS) penetration. Using this guideline, one of ordinary skill inthe art can choose the appropriate arylpiperazine moieties for aparticular THI moiety in order to ensure the bioavailability and CNSpenetration of a compound of the present invention. For example, if ahighly hydrophobic THI moiety is chosen, with particularly hydrophobicsubstituents, then a more hydrophilic arylpiperazine moiety can be used.

A number of compounds according to the present invention are opticallyactive, owing to the presence of chiral carbons or other centers ofasymmetry. In cases where compounds of the present invention areoptically active, all of the possible enantiomers or diastereoisomersare included unless otherwise indicated despite possible differences inactivity.

In general, the present compounds also include salts and prodrug estersof the compounds described herein. It is well known that organiccompounds, including substituted tetrahydroindolones, arylpiperazinesand other components of the present compounds, have multiple groups thatcan accept or donate protons, depending upon the pH of the solution inwhich they are present. These groups include carboxyl groups, hydroxylgroups, amino groups, sulfonic acid groups, and other groups known to beinvolved in acid-base reactions. The recitation of a compound in thepresent application includes such salt forms as occur at physiologicalpH or at the pH of a pharmaceutical composition unless specificallyexcluded.

Similarly, prodrug esters can be formed by reaction of either a carboxylor a hydroxyl group on the compound with either an acid or an alcohol toform an ester. Typically, the acid or alcohol includes an alkyl groupsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiarybutyl. These groups can be substituted with substituents such ashydroxy, halo, or other substituents. Such prodrugs are well known inthe art. The prodrug is converted into the active compound by hydrolysisof the ester linkage, typically by intracellular enzymes. Other suitablegroups that can be used to form prodrug esters are well known in theart.

Synthesis Methods

In order to synthesize the tetrahydroindolone derivatives describedherein, the tetrahydroindolone moiety is generally substituted with alinker which in turn is linked to the arylpiperazine moiety thatcompletes the molecule. This route comprises either the steps of: (1)synthesizing an appropriately substituted tetrahydroindolone moietylinked to an aliphatic linker in which the linker is terminated with ahalogen, and then reacting the halogen intermediate with thearylpiperazine to produce the final product; or (2) synthesizing anappropriately substituted arylpiperazine moiety linked to an aliphaticlinker in which the linker is terminated with a halogen, and thenreacting the halogen intermediate with the tetrahydroindolone to producethe final product.

Representative tetrahydroindazolone derivatives, as in formula (I) whenX is N, can be made from appropriately substituted cyclohexanedionescontaining R2 and R2′ substitutions via a two step procedure consistingof acylation with an acid chloride containing the R1 group in thepresence of an amine base, followed by cyclization with an appropriatelysubstituted arylpiperazine linked to a hydrazine moiety, usually heatedunder reflux in an aprotic solvent.

Another reaction that can be used to functionalize tetrahydroindolonesis the Mitsunobu reaction. The Mitsunobu reaction is a highly versatilemethod for the introduction of widely varying functional groups on thetetrahydroindolone moiety, because of the wide assortment of primary andsecondary alcohols that are commercially available for use in thisreaction.

The length of the aliphatic linker covalently bound to thetetrahydroindolone moiety can be varied to change the distance betweenthe tetrahydroindolone moiety and the arylpiperazine moiety in thecompounds of the present invention.

The arylpiperazinyl moiety of the present compounds can be synthesizedby a dihalide substitution reaction. Suitable substitution reactions aredescribed, e.g., in M. B. Smith & J. March, “March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure” (5^(th) ed.,Wiley-Interscience, New York, 2001).

Representative arylpiperazines can be made by those skilled in the artfrom appropriately substituted anilines via a substitution/cyclizationreaction with bis(2-chloroethyl)amine. The compounds are generally mixedin the presence of a base (acid scavenger) in a protic solvent (such asalcohol) and heated.

SYNTHESIS EXAMPLES

The following representative methods for synthesizing exemplaryembodiments of the present invention are merely intended as examples.Persons having ordinary skill in the art of medicinal and/or organicchemistry will understand that other starting materials, intermediates,and reaction conditions are possible. Furthermore, it is understood thatvarious salts and esters of these compounds are also easily made andthat these salts and esters can have biological activity similar orequivalent to the parent compound. Generally, such salts have halides ororganic acids as anion counterions. However, other anions can be usedand are considered within the scope of the present invention.

Example 1 Synthesis of1-{2-[4-(3,4-Dichlorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-oneStep 1: Preparation of1-(2-Chloroethyl)-4-(3,4-dichlorophenyl)piperazine

A mixture of (3,4-dichlorophenyl)piperazine (500 mg) and powdered sodiumhydroxide (87 mg) in DMSO (5 mL) was treated with 2-bromo-1-chloroethane(387 mg) and stirred at ambient temperature for 16 hours. The reactionwas poured into ice cold water (15 mL) and stirred for 0.5 hours. Asolid mass formed and was separated by decanting the water. The aqueouslayer was extracted with dichloromethane (5 mL). The solid mass wasdissolved with dichloromethane (5 mL) and the combined organics weredried with sodium sulfate, filtered and the solvent removed undervacuum. Flash chromatography (dichloromethane:methanol 1:0 to 10:1)yielded an oil (230 mg) as the titled compound.

Step 2:1-{2-[4-(3,4-Dichlorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one

To a solution of 1,5,6,7-tetrahyroindol-4-one (107 mg) in DMSO (2 mL)was added powdered sodium hydroxide (33 mg) and the mixture was stirredat ambient temperature for 0.5 hours.1-(2-Chloroethyl)-4-(3,4-dichlorophenyl)piperazine (220 mg) from step 1was then added as a solution in DMSO (2 mL) and the resulting mixturestirred at ambient temperature for 24 hours then heated to approximately60° C. for 2 hours, after which time thin layer chromatography (TLC)(ethyl acetate:dichloromethane 1:1) showed complete reaction. Thereaction was poured into ice cold water (15 mL) and stirred for 0.5hours. A solid mass formed and was separated by decanting the water. Theaqueous layer was extracted with dichloromethane (10 mL). The solid masswas dissolved with dichloromethane (5 mL) and the combined organics weredried with sodium sulfate and the solvent removed under vacuum to obtainan oil (250 mg) as the titled compound.

Step 3: Preparation of Oxalate salt of1-{2-[4-(3,4-Dichlorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol4-one

The compound from step 2 (250 mg) was dissolved in ethyl acetate (5 mL)using heat if required, and a solution of oxalic acid (57 mg) in acetone(0.5 mL) was added with stirring. A precipitate formed immediately andthe mixture was stirred for 0.5 hours at room temperature. Vacuumfiltration and washing with ethyl acetate afforded an off-white powderupon drying (220 mg).

The same 3-step procedure is used for all ethyl and propyl linkers.

Example 2 Synthesis of1-{4-[4-(3,4-Dichlorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-oneStep 1: Synthesis of 1-(4-Chlorobutyl)-1,5,6,7-tetrahydroindol-4-one

To a solution of 1,5,6,7-tetrahydroindol-4-one (10.0 g) in DMSO (100 mL)was added powdered sodium hydroxide (3.26 g) and the mixture was stirredat ambient temperature for 0.25 hours. 1-Bromo-4-chlorobutane (9.38 mL)was then added and the resulting mixture stirred at ambient temperaturefor 7 hours after which time TLC (ethyl acetate:dichloromethane 1:1)showed complete reaction. The reaction was poured into ice cold water(250 mL) and stirred for 0.5 hours. An oil separated and was isolatedwith a separatory funnel. The aqueous layer was extracted withdichloromethane (50 mL). The oil was dissolved with dichloromethane (25mL) and the combined organics were dried with sodium sulfate, filteredand the solvent removed under vacuum. Flash chromatography (ethylacetate:hexane, 1:1 to 2:1) yielded an oil (6.0 g) as the titledcompound.

Step 2: Synthesis of1-{4-[4-(3,4-Dichlorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one

A mixture of 1-(4-Chlorobutyl)-1,5,6,7-tetrahydroindol-4-one (600 mg)from step 1 and sodium iodide (438 mg) in acetonitrile (10 mL) washeated at reflux for 6 hours. (3,4-Dichlorophenyl)piperazine (581 mg)and potassium carbonate (367 mg) was then added and reflux continued for16 h. TLC (ethyl acetate:dichloromethane 1:1) showed complete reaction.The reaction was poured into ice cold water (50 mL) and stirred for 0.5hours. An oil separated out and was isolated from the mixture. The oilwas dissolved with dichloromethane (15 mL), washed with water and brine,then dried with sodium sulfate, filtered and the solvent removed undervacuum to yield the title compound as an oil (970 mg).

Step 3: Oxalate Salt Formation

Oxalate salt formation is done in the same manner as previouslydescribed.

The same 3-step procedure is used for all butyl linkers.

Treatments

Psychiatric Conditions

Psychiatric and neurological conditions can be treated by administeringtherapeutically effective amounts of the present compounds and/orpharmaceutical compositions. These compounds can be used asanti-psychotic compounds and administered to treat psychiatric disorderssuch as depression, anxiety including post traumatic stress syndrome,schizophrenia, schizoaffective disorders, bipolar disorders, sexualdysfunction, mood swings, sleep disorders, anorexia, bulimia, manicdepression, obsessive compulsive disorders, delusional post-partum,depression, postpartum psychosis, pre-menstrual syndrome, drug abuseassociated psychoses and combinations thereof. The present compounds canalso be used to enhance cognitive function and to treatneuroregenerative disorders with cognitive deterioration such asParkinson's disease, Huntington's disease, Alzheimer's disease, dementiaassociated with aging, and exposure to toxic chemical agents such assoman and saran.

The therapeutic effect of the compounds of the present invention isbelieved to be achieved by the ability of such compounds to affectmultiple neuroreceptors. These compounds are thus believed to comprisemultiple pharmacophores having different receptor activities. Forexample, the arylpiperazine moiety of the compounds is believed toaffect dopamine and serotonin (5-HT) receptors. In particular, thearylpiperazine derivatives contained in the compound are believed tohave dopamine D4 receptor antagonist activity and to have activity atother receptors including, but not limited to, dopamine D1, D2, and D3,as well as at serotonin receptors including but not limited to 5-HT1(A-F), S-HT2 (A-C), 5-HT3 (1-7), 5-HT4 C, 5-HT5 (A-B), 5-HT6, and 5-HT7.

Additionally, the tetrahydroindolone derivative moiety of the presentcompounds is believed to be a pharmacophore with GABA activity. As thoseskilled in the art will appreciate, GABA receptors are highly localizedin the hippocampal region of the brain which is associated with memory.Generally recognized GABA receptors include, but are not limited to GABAA alpha (1-6), GABA A beta (1-3), GABA A gamma (1-3), GABA A delta, GABAA pi, GABA A theta, GABA A rho (1-3), GABA B1 (a-c), GABA B2, and GABAC. Pharmacophores having GABA activity are believed to enhance cognitivefunction.

In another embodiment of the present invention, pharmaceutical compoundsdisclosed herein can selectively modulate dopamine, GABA and/orserotonin receptors, in particular D4 receptors. A compound that“selectively modulates” refers to one that interacts preferentially witha receptor causing increases or decreases in related neurologicalfunctions compared with its interaction with other receptors.

Emotional, mood swings and cognitive disorders related to psychiatricdisturbances that are expressed as sleep disorders, anorexia, bulimia,postpartum depression, post-partum psychosis, pre-menstrual syndrome,manic depression, obsessive compulsive disorders, and delusionaldisorders can also be treated using the present compounds andpharmaceutical compositions. Other emotional disturbances that can beeffectively treated include those related to substance abuse. Forexample, the present pharmaceutical compositions can be used to preventdrug dependence or tolerance including that produced by nicotine,opioids such as morphine, cocaine and barbiturates such as diaxepam.Furthermore, the pharmaceutical compositions of the present inventioncan be useful in preventing or treating emotional and cognitivedisturbances or psychoses associated with drug withdrawal or cessationtolerance including that produced by nicotine, opioids such as morphine,cocaine and barbiturates such as diaxepam.

Cognitive and other neurological disorders that can be effectivelytreated using the present compounds and pharmaceutical compositionsinclude conditions such as, but not limited to, neurosensory diseasesand injury, Parkinson's disease and other movement disorders such asdystonia, Wilson's disease, inherited ataxias, Tourette syndromecerebral palsy, encephalopathies. Other cognitive conditions that can betreated include cognitive and attention deficit disorders associatedwith acquired immunodeficiency syndrome (AIDS), dementia, ischemicstroke, chemical exposure, and cardiac bypass associated cognitivedefects.

The present invention thus includes the use of the present compounds ina pharmaceutical composition to treat psychiatric and neurologicalconditions as described above. In addition, the invention includes theuse of these compounds for the manufacture of a medicament for thetreatment of such psychiatric and neurological conditions.

Pain

Pain can be effectively treated with the compounds and pharmaceuticalcompositions of the present invention by administering an effectiveamount of these compounds and/or compositions to a patient in needthereof, in particular by administering an analgesic dosage of thesecompositions. Among the different types of pain that can be treated withthe present compounds are acute pain, chronic pain, nociceptive pain(i.e., pain associated with pain transmission through intact nerveendings), and neuropathic pain (caused by nervous system dysfunction andcharacterized by burning, shooting, and tingling pain, associated withallodynia, hyperpathia, paresthesias and dysesthesias). Conditions whichcan involve acute pain include headache, arthritis, simple musclestrain, and dysmenorrhea. Nociceptive pain can include, e.g.,post-operative pain, cluster headaches, dental pain, surgical pain, painresulting from burns, post partum pain, angina pain, genitourinary tractrelated pain, cystitis, pain associated with arthritis, AIDS, chronicback pain, visceral organ pain, gastroesophageal reflux, peptic ulcers,infectious gastritis, inflammatory bowel disorders, misname headaches,tension headaches, fibromyalgia, nerve root compression such assciatica, trigeminal neuralgia, central pain, bone injury pain, painduring labor and delivery, muscle strain, alcoholism, herpeticneuralgia, phantom limb paw and dysmenorrheal pain. Conditions involvingneuropathic pain include chronic lower back pain, pain associated witharthritis, cancer-associated pain, herpes neuralgia, phantom limb pain,central pain, opioid resistant neuropathic pain, bone injury pain, andpain during labor and delivery. Relief from pain-induced psychiatricdisorders such as anxiety, depression and/or severe mood changes as wellas emetic responses related to pain and its treatment can also beprovided with the present compounds and compositions.

In one embodiment, the compounds of the present application can becombined with other analgesics to form a pharmaceutical composition, inorder to lower the dose of the present compounds required to relievepain and/or to achieve a synergistic reduction in pain experienced by apatient. Other analgesics which can be co-administered with the presentcompounds (either at the same time or at different times) includeaspirin, ibuprophen, acetaminophen, opiates, acetaminophen combined withcodeine, indomethacin, tricyclic antidepressants, anticonvulsants,serotonin reuptake inhibitors, mixed serotonin-norepinephrine reuptakeinhibitors, serotonin receptor agonists and antagonists, cholinergicanalgesics, adrenergic agents, and neurokinin antagonists. Otheranalgesics may be found, for example, in the Merck Manual, 16th Ed.(1992) p. 1409.

The present invention thus includes the use of the present compounds ina pharmaceutical composition to treat pain. In addition, the inventionincludes the use of these compounds for the manufacture of a medicamentfor the treatment of pain.

Emesis

The compounds and pharmaceutical compositions of the present applicationare also useful in alleviating both motion- and toxin-induced emesis, byadministering an effective amount of these compounds and/or compositionsto a patient in need thereof. Motion sickness as well as emesisassociated with the administration of chemotherapeutic agents such ascisplatin, dacarbazine, cyclophosphamide, 5-fluorouracil, doxorubicinand paclitaxol or toxic agents such as soman or sarin can be treated. Itis believed that the present compounds can be useful both for motionsickness and for chemical-induced nausea because they have 5-HT1Areceptor agonist activity. There are currently no known stategics oragents that are effective in blocking emesis caused from a variety ofdifferent stimuli. For example, agents that are known to be effective inblocking motion sickness have not been found to be effective againstemesis that is induced chemically.

The present invention thus includes the use of the present compounds ina pharmaceutical composition to treat emesis. In addition, the inventionincludes the use of these compounds for the manufacture of a medicamentfor the treatment of emesis.

Neuroregeneration

An additional use of the present compounds and/or pharmaceuticalcompositions is in stimulating neurogenesis, neuronal regeneration oraxo-dendritic complexity in the central and peripheral nervous systems.This is accomplished through the step of administering an effectiveamount of a compound according to the present invention to a subject inneed thereof. Such neuroregenerative effects are believed to be theresult of the 5-HT1A receptor agonist activity of the compounds.Neurodegenerative conditions that can be treated can be genetic,spontaneous or iatrogenic, including, but not limited to, stroke, spinalcord injury amyotrophic lateral sclerosis, perinatal hypoxia, oculardamage and retinopathy, ocular nerve degeneration, hearing loss,restless leg syndrome, Gulf War Syndrome and Tourette's syndrome. Anexample of a drug therapy that is currently used to treat theneurodegenerative disease ALS is the 5-HT1A agonist xaliproden.

The compounds of the present invention can also be used to treatperipheral neuropathies. Examples of diseases associated with peripheralneuropathies include, but are not limed to, acromegaly, hypothyroidism,AIDS, leprosy, Lyme disease, systemic lupus erythematosus, rheumatoidarthritis, Sjogren's Syndrome, periarteritis nodosa, Wegener'sgranulomatosis, cranial arteritis, sarcoidosis, diabetes, vitamin B12deficiency, cancer, Gulf War Syndrome and alcoholism. Examples of drugtherapies associated with peripheral neuropathies include, but are notlimed to oncolytic drugs such as a vinca alkaloid, platinum derivativessuch as cisplatin, paclitaxel, suramin, altretamine, carboplatin,chlorambucil, cytarabine, dacarbazine, docetaxel, etoposide,fludarabine, ifosfamide with mesna, tamoxifen, teniposide, orthioguanine.

The present invention thus includes the use of the present compounds ina pharmaceutical composition to treat neurodegeneration or injury. Inaddition, the invention includes the use of these compounds for themanufacture of a medicament for the treatment of neurodegeneration orinjury.

Neuroprotection and Use as Biodefense Agent

An additional aspect of the present invention is a method of stimulatingneuronal function involving a mechanism associated withneuroprotection/neuroregeneration in the central or peripheral nervoussystem of a subject, comprising the step of administering an effectiveamount of the present compounds and pharmaceutical compositions to thesubject. Compounds in this series can be useful in providingneuroprotection against exposure to chemical organo-phosphorus nerveagents. These compounds are believed to target multiple brain substratesexpected to have synergistic action in the treatment of multipletoxicities as a result of chemical exposure in biodefense.

Acute high dose exposure to chemical agents results in seizures and/ordeath. Lower level exposure can result in what has been termed Gulf WarSyndrome, which includes neuronal cell loss, acute and/or delayedcognitive impairment, acute and/or delayed attention impairment, andperipheral neuropathy. Other potential indications from exposure tochemical agents include emesis and anxiety.

The present invention thus includes the use of the present compounds ina pharmaceutical composition to provide neuroprotection. In addition,the invention includes the use of these compounds for the manufacture ofa medicament for providing neuroprotection.

Dosing

Depending upon the particular needs of the individual subject involved,the compounds of the present invention can be administered in variousdoses to provide effective treatment concentrations based upon theteachings of the present invention. Factors such as the activity of theselected compounds, the physiological characteristics of the subject,the extent or nature of the subjects disease or condition, and themethod of administration will determine what constitutes an effectiveamount of the selected compounds. Generally, initial doses will bemodified to determine the optimum dosage for treatment of the particularsubject. The compounds can be administered using a number of differentroutes including oral administration, topical administration,transdermal administration, intraperitoneal injection, or intravenousinjection directly into the bloodstream. Effective amounts of thecompounds can also be administered through injection into thecerebrospinal fluid or infusion direly into the brain, if desired.

An effective amount of any embodiment of the present invention isdetermined using methods known to pharmacologists and clinicians havingordinary skill in the art. For example, a pain relieving effectiveamount can be determined subjectively by administering increasingamounts of the pharmaceutical compositions of the present inventionuntil such time the patient being treated reports diminishment in painsensations. Blood levels of the drug can be determined using routinebiological and chemical assays and these blood levels can be matched tothe route of administration. The blood level and route of administrationgiving the most desirable level of pain relief can then be used toestablish an “effective amount” of the pharmaceutical composition fortreating the pain under study. This same method of titrating apharmaceutical composition in parallel with administration route can beused to ascertain an “effective amount” of the pharmaceuticalcompositions of the present invention for treating any and allpsychiatric or neurological disorders described herein. In addition,animal models as described below can be used to determine applicabledosages for a particular condition.

Exemplary dosages in accordance with the teachings of the presentinvention for these compounds range from 0.0001 mg/kg to 60 mg/kg,though alternative dosages are contemplated as being within the scope ofthe present invention. Suitable dosages can be chosen by the treatingphysician by taking into account such factors as the size, weight, age,and sex of the patient, the physiological state of the patient, theseverity of the condition for which the compound is being administered,the response to treatment, the type and quantity of other medicationsbeing given to the patient that might interact with the compound, eitherpotentiating it or inhibiting it, and other pharmacokineticconsiderations such as liver and kidney function.

Animal Models

In determining the therapeutic effects and appropriate dosages ofparticular compounds and pharmaceutical compositions according to thepresent application for a human subject, animal models can be used.Exemplary animal models are set forth below.

The following representative set of compounds of the present applicationwas tested in various animal models:

-   1-{4-[4-(4-Fluorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one-   1-{4-[4-(3,4-Dichlorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one-   1-{2-[4-(3,4-Difluorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one-   1-{4-[4-(3,4-Dimethylphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one    Tail Flick Test (Pain Model)

Tail-flick has been used to define or monitor analgesic levels followingexposure to a variety of compounds (D'Amour and Smith, 1941; Harris andPierson, 1964). It can be used to test mice, rats or monkeys by focusinga beam of light on the tail and evaluating latency to tail-flick. Thistest has proven useful for screening weak or strong analgesics (Deweyet. al., 1969). The representative compounds listed above were effectivein relieving the hard pain induced by a focused beam of light on thetail. An analgesic effect was determined for three of the four compoundstested.

Mouse Writhing Test (Pain Model)

An accepted standard for detecting and comparing the analgesic activityof different classes of analgesic compounds for which there is a goodcorrelation with human analgesic activity is the prevention of aceticacid induced writhing in mice. R. Koster et al., Acetic acid foranalgesic screening. Fed. Proc. 18:412 (1959).

Mice, treated with various doses of the present compounds and incombination with another analgesic or with vehicle are injectedintraperitoneally with a standard challenge dose of acetic acid 5minutes prior to a designated observation period. The acetic acid isprepared as a 0.55% solution and injected at a volume of 0.1 ml/10 gramsof body weight. For scoring purposes a “writhe” is indicated by wholebody stretching or contracting of the abdomen during an observationperiod beginning about five minutes after the administration of aceticacid. The representitive compounds listed above were effective inrelieving the soft pain induced by acetic acid.

Hot Plate Test (Pain Model)

Hot plate is used as a test for drug-induced analgesia to thermal pain.In the performance of this test, a mouse or rat is placed on a heatedplate. The latency for the animal to demonstrate a pain response to theheated plate is measured. Pain responses can include hindpaw withdrawalfrom the plate associated with hindpaw licking or other nocifensivebehaviors. A drug-induced delayed latency is indicative of an analgesicresponse. The representitive compounds listed above were effective inincreasing the latency to pain response in the hot plate test.

Plantar Formalin Test (Rain Model)

A subcutaneous injection of a formalin solution into the ventral, orplantar, surface of a rat or mouse hindpaw can induce an acute painresponse in the treated paw. The response can include hindpaw withdrawalfrom the floor associated with hindpaw licking. The time the animalmaintains the hindpaw withdrawal from the floor and the number of timesthe animal turns to lick the hindpaw are measures of pain. An analgesiccompound reduces the withdrawal time and number of paw licks. Compoundsfrom this series were effective in reducing the behaviors induced byplantar formalin injection.

Other clinically acceptable pain models can also be used to determinethe effects or dosing of a particular compound for use in treating pain,including the following: Chung/Bennett Model; Hargreaves Test;Mechanical Allodynia (von Frey); Paw Plethysmograph Test;Intraperitoneal Irritant Injection-Induced Writhing Test.

Induction and Measurement of Chemotherapy-Induced Emesis (Emesis Model)

Male or female S. murinus (30-80 g) are maintained in atemperature-controlled room at 24±1 C under artificial lighting, withlights on between 0700 and 1730 hours. Artificial humidity is maintainedat 50±5%. Animals are allowed free access to water and pelleted cat chow(e.g., Feline Diet 5003, PMI® Feeds, St Louis, USA).

On the day of experiment, the animals are transferred to clearobservation chambers (approximately 21×14×13 cm) for the assessment ofemetic behavior. They are allowed 30 minutes to adapt before beinginjected subcutaneously with compounds or their respective vehicles.Chemotherapy emetic agents are administered intravenously followingadministration of test compounds. The animals are then observed for 60minutes. An episode of emesis is characterized by rhythmic abdominalcontractions that are either associated with the oral expulsion of solidor liquid material from the gastrointestinal tract (i.e. vomiting) ornot associated with the passage of material (i.e. retching movements).An episode of retching and/or vomiting is considered separate when ananimal changed its location in the observation chamber, or when theinterval between retches and/or vomits exceeded 2 seconds. Compounds inthis series are effective in blocking chemotherapy-induced emesis.

Induction and Measurement of Motion-Induced Emesis (Emesis Model)

To test for emesis due to motion exposure, animals are placed in atransparent cage on a reciprocal shaker (e.g., Taitec, Double ShakerR-30, Taiyo Scientific Industrial Co Ltd.) after an acclimatizationperiod of at least 5 minutes. Compounds are administered atpredetermined time points before testing. The animals are exposed tohorizontal motion of 4 cm displacement (2 cm left, 2 cm right) at afrequency of 1 Hz for 10 minutes. A 10 minute exposure is used to reducethe chances of obtaining a false negative result. Observation iscontinued for at least 5 minutes after the end of motion exposure incase a delayed response occurs, although previous studies have shownthat episodes of emesis after cessation of motion are very rare.Compounds in this series are effective in blocking motion-inducedemesis.

Pre-Pulse Inhibition Testing (Schizophrenia/Psychosis Model)

The non-competitive NMDA receptor antagonist phencyclidine (PCP) reducespre-pulse inhibition (PPI) of the acoustic startle response in rodents.Compounds that improve the PCP-induced deficits in pre-pulse inhibitioncan be useful for treating schizophrenia. In this test, male C-57 miceare assigned to five dose groups of eight animals per group, and vehicleor test compound are administered orally (PO) or subcutaneously (SC) 20minutes prior to intraperitoneal (EP) administration of vehicle or PCP(5 mg/kg). Ten minutes following PCP administration, the mice are placedinto Hamilton-Kinder startle chambers and evaluated. Following afive-minute acclimatization period with background white noise (65 db),mice are exposed to five different trial types. Trials were presentedten-time search in a quasi-random order, with randomized 5 to 25 secondinter-trial intervals. The trials are: stimulus only trial (120 db whitenoise, 50 ms stimulus); two different prepulse+pulse trials in which a20 ms 5 db, or 10 db stimuli above a 65 db background preceded the 120db pulse by 120 ms; a 10 db prepulse without a 120 db pulse; and a nostimulus trial, in which only the background noise was presented.Reversal of disruption of pre-pulse inhibition produced by PCP is aclinical predictor of compounds with antipsychotic activity.

Conditioned Avoidance Testing (Schizophrenia/Psychosis Model)

The Condition Avoidance Responding (CAR, active avoidance) model testsfor antipsychotic activity. The disruption of avoidance (increasedlatency) without disruption of escape (extrapyramidal motor function) isa clinical predictor of compounds with antipsychotic activity. Trainingof animals (mice) consists of 20 trials with variable inter-trialintervals (trained to 80% Avoidance Criteria). After a one-minuteacclimation period, the house light and an acoustic 90 dB tone(conditioned stimuli) are presented. A response (crossing to darkcompartment) within 5 seconds ends the trial and trial is recorded asavoidance response (CAR). If the mouse does not respond within 5seconds, foot shock (0.8 mA) is presented, and the response (moving tothe dark chamber) during the shock was recorded as an escape response.To avoid shock, animals learn to move from the lighted side of the-chamber to the dark side when the cue is presented (avoidance) or movedwhen the shock is administered (escape). Vehicle or test compounds areadministered subcutaneously 20 minutes before the test session. Thischecks for disruption of cognition and attention.

Other clinically acceptable models of schizophrenia and/or otherpsychiatric conditions can also be used to determine the effects ordosing of a particular compound for use in treating psychosis, includingthe following: Amphetamine-, Cocaine-, PCP-, or MK-801-InducedHyperlocomotion; Catalepsy, and MK-801-Induced Locomotion and Falling.

Potentiated Startle (Anxiety Model)

Hamilton-Kinder startle chambers were used for conditioning sessions andfor the production and recording of startle responses. A classicalconditioning procedure was used to produce potentiation of startleresponses. Briefly, on the first 2 days, rats were placed into darkstartle chambers in which shock grids were installed. Following a5-minute acclimation period, each rat received a 1 mA electric shock(500 ms) preceded by a 5 second presentation of light (15 watt) whichremained on for the duration of the shock. Ten presentations of thelight and shock were given in each conditioning session, rats weregavaged with a solution of test compound of water and startle testingsessions were conducted. A block of 10 consecutive presentations ofacoustic startle stimuli (110 dB, non-light-paired) were presented atthe beginning of the session in order to minimize the influences of theinitial rapid phase of habituation to the stimulus. This was followed by20 alternating trials of the noise alone or noise preceded by the light.Excluding the initial trial block, startle response amplitudes for eachtrial type (noise−alone vs. light+noise) were averaged for each ratacross the entire test session. Data are presented as the differencebetween noise−alone and light+noise. Compounds that reduce or blockpotentiated startle are considered to have anxiolytic activity.

Automated Elevated Plus Maze (Anxiety Model)

The Hamilton-Kinder elevated plus-maze is based on the design of Heltonet al., and was originally validated for mice by Lister (1987). The mazecan be made of Plexiglas having two open arms (e.g., 30×5×0.25 cm) andtwo enclosed arms (30×5×15 cm). The floor of each maze arm is corrugatedto provide texture. The arms extend from a central platform and angledat 90 degrees from each other. The maze iss elevated to a height of 45cm above the floor and illuminated by red light. Individual infraredphotocells are mounted along each arm of the maze to monitor closed,open, or nosepoke activity. Mice are individually placed on the centralplatform of the maze and the number of closed arm, open arm, andnosepoke (poking head only into open arm from closed arm of maze) countsare recorded and used as a measure of arm entries and time spent onvarious sections of the maze over a five-minute test period.Administration of the present compounds can increase open arm activityindicating anxiolytic activity.

Other clinically acceptable models of anxiety can also be used todetermine the effects or dosing of a particular compound for use intreating anxiety, including the Light/Dark Exploration and MaternalSeparation Vocalization Tests.

Tail Suspension Test (Depression Model)

The tail suspension test is a variant of the “behavioral despair” forcedswimming test in which immobility is induced by suspending an animal bythe tail (Steru et al., 1985). The chamber was 17 cm W×25 cm H×15 cm Dwith a hook (4 cm) attached to the center of the ceiling. There was nofront wall to allow for the observation of the mouse behavior. The mousewas hung on a hook by an adhesive tape placed 15 mm from the extremityof its tail. The animal was positioned with its stomach towards theinvestigator to assure the observation of the total immobility.Immobility was scored as a sum of the time periods during which theanimal hung passively and motionless for at least 2 sec. The totalperiod of observation was 6 min. Administration of the representitivecompounds listed above was effective in reducing immobility in the test.

Other clinically acceptable models of depression can also be used todetermine the effects or dosing of a particular compound for use intreating depression, including the Forced Swim Test and DRL Test.

Measures of CNS Activity

Acoustic startle is a test for sensorimotor reactivity and can be usedto profile the potential for drug-induced adverse side-effects. Acousticstartle is measured as the maximum force (N) transduced to a plate inresponse to a 120 dB stimulus. Hamilton-Kinder startle chambers wereused to present the startle stimulus and measure and record theresponse. Animals were presented a block of 20 consecutive acousticstimuli and the responses were averaged. A drug-induced increase inresponse can indicate the potential for an adverse event such asanxiogenic potential for that dose. A drug-induced decrease in responsecan indicate, the potential for an adverse event such as sedation forthat dose. The representitive compounds listed above do not induce asignificant increase or decrease in acoustic startle response atefficacy doses tested. At higher than efficacy doses, compounds fromthis series induce a dose dependent decrease in acoustic startle.

Ambulatory and non-ambulatory activity is used to test spontaneous anddrug-induced motor activity. The test can be used to profile thepotential for a drug to induce hyperactivity or sedation. AHamilton-Kinder photobeam activity monitors were used to record theambulatory and non-ambulatory motor activity of mice and rats. Themonitors track the photobeam breaks made by the animal that are used tocalculate the number of ambulatory and fine (non-ambulatory) motormovements. A drug-induced increase in activity can indicate thepotential for an adverse event such as hyperactivity. A drug-induceddecrease in response can indicate the potential for an adverse eventsuch as sedation. Compounds from this series do not induce a significantincrease or decrease in activity at efficacy doses tested. At higherthan efficacy doses, compounds from this series induce a dose dependentdecrease in activity.

Additional Models

Other clinically accepted models of neurological conditions known to theart can also be used to determine the therapeutic effects andappropriate dosages of particular compounds and pharmaceuticalcompositions according to the present application. These include, interalia, the following tests.

Learning Memory Models: Acquisition of Fear Potentiated Startle; PassiveAvoidance, Shuttle or Step Down; Acquisition of Active Avoidance; MorrisWater Maze; and Amnesic Reversal.

Attention Deficit Models: ADHD Young Animal Model (PPI and Activity);ADD Aged Animal Model; and Acquisition of Active Avoidance Model.

Neuroprotectuon/Epilepsy: Pentylenetetrazol-, Strychnine-, Bicuculine-,Picrotoxin-Induced Convulsions, sarin and soman and MES/ECS.

Parkinson's Disease: Apomorphine-, Amphetamine-Induced Rotations(6-OHDA); and Reserpine-Induced Hypothermia/Hypolocomotion.

Drug Dependence and Withdrawal: Nicotine-, Benzodiazepine-, andEthanol-Induced Withdrawal.

Pharmaceutical Compositions

Another aspect of the present invention is a pharmaceutical compositionthat comprises: (1) an effective amount of a compound according to thepresent invention as described above (including salts and estersthereof); and (2) a pharmaceutically acceptable excipient.

A pharmaceutically acceptable excipient, including carriers, can bechosen from those generally known in the art including, but not limitedto, inert solid diluents, aqueous solutions, or non-toxic organicsolvents, depending on the route of administration. If desired, thesepharmaceutical formulations can also contain preservatives andstabilizing agents and the like, for example substances such as, but notlimited to, pharmaceutically acceptable excipients selected from thegroup consisting of wetting or emulsifying agents, pH buffering agents,human serum albumin, antioxidants, preservatives, bacteriostatic agents,dextrose, sucrose, trehalose, maltose, lecithin, glycine, sorbic acid,propylene glycol, polyethylene glycol, protamine sulfate, sodiumchloride, or potassium chloride, mineral oil, vegetable oils andcombinations thereof. Those skilled in the art will appreciate thatother carriers also can be used.

Liquid compositions can also contain liquid phase excipients either inaddition to or to the exclusion of water. Examples of such additionalliquid phases are glycerin, vegetable oils such as cottonseed oil,organic esters such as ethyl oleate, and water-oil emulsions.

Formulations suitable for parenteral administration, such as, forexample, by intravenous, intramuscular, intradermal, and subcutaneousroutes, include aqueous and non-aqueous isotonic sterile injectionsolutions. These can contain antioxidants, buffers, preservatives,bacteriostatic agents, and solutes that render the formulation isotonicwith the blood of the particular recipient. Alternatively, theseformulations can be aqueous or non-aqueous sterile suspensions that caninclude suspending agents, thickening agents, solubilizers, stabilizers,and preservatives. The pharmaceutical compositions of the presentinvention can be formulated for administration by intravenous infusion,oral, topical, intraperitoneal, intravesical, transdermal, intranasal,rectal, vaginal, intramuscular, intradermal, subcutaneous andintrathecal routes.

Formulations of compound suitable for use in methods according to thepresent invention can be presented in unit-dose or multi-dose sealedcontainers, in physical forms such as ampules or vials. The compositionscan be made into aerosol formations (i.e., they can be “nebulized”) tobe administered via inhalation. Aerosol formulations can be placed intopressurized acceptable propellants, such as dichloromethane, propane, ornitrogen. Other suitable propellants are known in the art.

Although the present invention has been discussed in considerable detailwith reference to certain preferred embodiments, other embodiments arepossible. Therefore, the scope of the appended claims should not belimited to the description of preferred embodiments contained in thisdisclosure. All references cited herein are incorporated by reference totheir entirety. In addition, all groups described herein can beoptionally substituted unless such substitution is excluded.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember can be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group can be included in, ordeleted from, a group.

1. A pharmaceutical composition comprising a compound having thefollowing formula (I):

wherein: (a) X is CH or N; (b) R₁ is hydrogen, alkyl, aralky,heteroaralkyl, alkenyl, aralkenyl, heteroaralkenyl, aryl, or heteroaryl;(c) R₂ is hydrogen, alkyl, aralky, aryl, or heteroaryl; (d) R₂ ishydrogen unless R₂ is methyl, in which case R₂ is also methyl; (e) R₃has the following formula (III):

wherein: (i) R₄ is hydrogen, alkyl, halo, hydroxy, alkoxy, cyano, nitro,perfluoroalkyl, perfluoroalkoxy, or hydroxymethyl; (ii) R₅ is hydrogen,alkyl, halo, alkoxy, cyano, nitro, perfluoroalkyl, perfluoroalkoxy,amino, aminocarbonyl, aminosulfonyl, or hydroxymethyl; (iii) R₆ isalkyl, halo, alkoxy, perfluoroalkyl, perfluoroalkoxy, or nitro; (iv) R₄and R₅ when taken together can form a 5 or 6 membered ring and cancontain one or more heteroatoms; (v) R₅ and R₆ when taken together canform a 5 or 6 membered ring and can contain one or more heteroatoms; (f)L is selected from the group consisting of —(CH₂)_(m)—, where m is aninteger from 1 to 6, and an alkyl substituted hydrocarbyl moiety of theformula (IV):

wherein: (i)_(n) is 0, 1 or 2; (ii) R7 and R8 are hydrogen, methyl orethyl; (iii) R9 and R9′ are both hydrogen, methyl or ethyl; (iv) if n is1 and R7 or R8 is methyl or ethyl, then R9 and R9′ are hydrogen; (v) ifn is 1 and R7 and R8 are hydrogen, then R9 and R9′ are methyl or ethyl;and (vi) if n is 2, then R9 and R9′ are hydrogen and one or both of R7and R8 are methyl or ethyl. and pharmaceutically acceptable salts andesters thereof.
 2. The pharmaceutical composition of claim 1, wherein R₂and R₂, are both hydrogen.
 3. The pharmaceutical composition of claim 1,wherein R₄ is selected from the group consisting of hydrogen, halo, andalkoxy.
 4. The pharmaceutical composition of claim 1, wherein R₅ isselected from the group consisting of hydrogen, alkyl, halo, alkoxy, andperfluoroalkyl;
 5. The pharmaceutical composition of claim 1, wherein R₆is selected from the group consisting of alkyl, halo, alkoxy, andperfluoroalkyl.
 6. The pharmaceutical composition of claim 1, wherein R₄and R₅ when taken together form a naphthalene ring; and
 7. Thepharmaceutical composition of claim 1, wherein R₅ and R₆ when takentogether are selected from the group consisting of a methylenedioxygroup and an ethylenedioxy group.
 8. The pharmaceutical composition ofclaim 1, wherein L is an alkyl substituted hydrocarbyl moiety of formula(IV).
 9. The pharmaceutical composition of claim 1, comprising apharmaceutically acceptable excipient.
 10. A method of treating apsychiatric or neurological condition, comprising the step ofadministering a therapeutic dose of the pharmaceutical composition ofclaim 1 to a patient in need thereof.
 11. The method of claim 10,wherein the therapeutic dose is administered by an administrative routeselected from the group consisting of intravenous infusion, oral,topical, intraperitoneal, intravesical, transdermal, nasal, rectal,vaginal, intramuscular, intradermal, subcutaneous and intrathecalroutes.
 12. The method of claim 10, wherein the therapeutic dose is inthe range of 0.0001 mg/kg to 60 mg/kg.
 13. The method of claim 10,wherein the condition being treated is a psychiatric condition.
 14. Themethod of claim 10, wherein the condition being treated is pain.
 15. Themethod of claim 10, wherein the condition being treated is emesis. 16.The method of claim 10, wherein the condition being treated isneurodegeneration. 17-18. (canceled)